Methylated cyclodextrin complexes

ABSTRACT

The present invention is directed to novel complexes of cyclodextrin. In particular the invention is directed to a complex of a cyclodextrin selected from the group consisting of RM-β-cyclodextrin, DM-β-cyclodextrin and TM-β-cyclodextrin, and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrhydrocannabinol and cannabidiol.

TECHNICAL FIELD OF THE INVENTION

The present invention describes the use of methylated cyclodextrins(CDs) in order to improve the aqueous solubility, dissolution rate andbioavailability of selected cannabinoids, especially classicalcannabinoids such as Δ⁹-tetrahydrocannabinol (THC). In addition,methylated CDs provide a means to prepare liquid and solid formulationsof cannabinoids which can be used in various dosage forms, such as fororal administration, including sublingual and buccal administration, butalso nasal and pulmonary administration, parenteral, and topicaladministration.

BACKGROUND OF THE INVENTION

Cannabinoids are a group of compounds which are ligands to cannabinoidreceptors (CB₁, CB₂) found in the human body (Pertwee, 1997).Cannabinoids were originally found from Cannabis Sativa L., an origin ofmarijuana and hashish. Over the last few years, marijuana or itscomponents have been reported in scientific literature to counter thesymptoms of a broad range of conditions including multiple sclerosis andother forms of muscular spasm, including uterine and bowel cramps;movement disorders; pain, including migraine headache; glaucoma, asthma,inflammation, insomnia, and high blood pressure. There may also beutility for cannabinoids as an oxytoxic, anxiolytic, anti-convulsive,anti-depressant and anti-psychotic agent (Williamson and Evans, 2000),anti-cancer agent, as well as an appetite stimulant.

Nowadays over 60 chemically related compounds, collectively classifiedas cannabinoids, have been isolated from Cannabis Sativa L., includingtetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). Inaddition, various synthetic ligands for cannabinoid receptors have beendeveloped during the last years. The cannabinoids are usually divided inthe groups of classical cannabinoids, non-classical cannabinoids,aminoalkylindol-derivatives and eicosanoids (Pertwee, 1997). Classicalcannabinoids are isolated from Cannabis Sativa L. or they can comprisesynthetic analogs of these compounds. Non-classical cannabinoids arebi-or tricyclic analogs of tetrahydrocannabinol (THC) (without the pyranring); aminoalkylindols form a group which differs structurallysubstantially from classical and non-classical cannabinoids.

The pharmacological and toxicological studies of cannabinoids have beenfocused mainly on THC (commercially available by the name Dronabinol)which in 1985 was approved by FDA for the treatment of chemotherapyassociated nausea and vomiting, and later for AIDS-associated wastingand anorexia. Dronabinol is a synthetic analog of THC which is marketedin USA as Marinol. In Marinol, THC is dissolved in sesame oil and it isadministered orally as a capsule containing 5 or 10 mg of THC. The majorproblem of THC in oral administration is its low bioavailability due toits poor dissolution properties and high first pass metabolism. Thebioavailability of orally ingested THC ranges from only 6% toapproximately 20% depending on the drug vehicle employed.

Cyclodextrins (CDs) are cyclic oligosaccharides consisting of(α-1,4)-inked α-D-glucopyranose units, with a lipophilic central cavityand a hydrophilic outer surface (Frömming and Szejtli, 1994). CDs areable to form inclusion complexes with many drugs by taking up the wholedrug, or more commonly, the lipophilic moiety of the molecule, into thecavity. The most abundant natural CDs are α-cyclodextrin (α-CD),β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD), containing six, seven,and eight glucopyranose units, respectively. Of these three CDs, β-CDappears to be the most useful pharmaceutical complexing agent because ofits cavity size, availability, low cost and other properties. Since β-CDhas limited aqueous solubility, numerous water-soluble β-CD derivativeshave been synthesized, including hydroxypropyl-β-cyclodextrin (HP-β-CD),sulfobutylether-β-cyclodextrin (SBE-β-CD), maltosyl-β-cyclodextrin(ML-β-CD) and methylated CDs, including dimethyl-β-cyclodextrin(DM-β-CD), trimethyl-β-cyclodextrin (TM-β-CD) and randomly methylatedβ-cyclodextrin (RM-β-CD).

In drug formulations, CDs have been used mainly to increase the aqueoussolubility, stability and bioavailability of various drugs, foodadditives and cosmetic ingredients (Frömming and Szejtli, 1994). Inaddition, CDs can also be used to convert liquid compounds intomicrocrystalline powders, prevent drug-drug or drug-additiveinteractions, reduce gastro-intestinal or ocular irritation, and reduceor eliminate unpleasant taste and smell.

Studies dealing with the use of CDs with cannabinoids (classical,non-classical and aminoalkylindol derivatives) are referred to in thefollowing publications. Shoyama et al. (1983) have reported that THCforms an inclusion complex with natural β-CD with increasing chemicalstability of THC. Shoyama et al. (1983) prepared the solid THC/β-CDinclusion complex by mixing THC and β-CD in methanol/water solution andhypothesised that CDs may also be used to improve the aqueous solubilityand membrane permeability of THC. Jarho et al. (1998) have reported thatHP-β-CD increases the aqueous solubility of THC and co-administration ofsmall amounts of water-soluble polymer (HPMC) enhances the complexationbetween HP-β-CD and THC. In addition, Song et al. (2000) and Porcella etal. (2001) have recently used HP-β-CD to solubilize the aminoalkylindolderivative WIN-55212 in topical ophthalmic formulations.

SUMMARY OF THE INVENTION

The present invention is directed to a novel complex between a specificgroup of cyclodextrins and cannabinoids. Specifically, the inventionrelates to a complex of a cyclodextrin selected from the groupconsisting of RM-β-cyclodextrin, DM-β-cyclodextrin andTM-β-cyclodextrin, and a cannabinoid selected from the classicalcannabinoid-group consisting of cannabinol, tetrahydrocannabinol andcannabidiol.

The invention is also directed to a method of preparing such a complex,as well as to pharmaceutical compositions containing such a complex. Thecomplexes or the pharmaceutical compositions containing the same areespecially intended for administration through a mucous membrane, suchas for sublingual or buccal administration in the form of a tablet,capsule, solution or spray, although also other manners ofadministration can come into question, such as other oral administrationforms, e.g. in the form of tablets and capsules to be swallowed, or inthe form of e.g. solutions or solid powders for pulmonary and nasaladministration. Also parenteral and topical administration iscontemplated, the latter form of administration including the use of thecomplex for ophthalmic administration.

Furthermore the invention is directed to a method for treating anindividual, such as a human, for a condition responsive to treatmentwith a cannabinoid, the method comprising administering to saidindividual a sufficient amount of a complex of a cyclodextrin selectedfrom the group consisting of RM-β-cyclodextrin, DM-β-cyclodextrin andTM-β-cyclodextrin, and a cannabinoid selected from the classicalcannabinoid-group consisting of cannabinol, tetrahydrocannabinol andcannabidiol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of RM-β-CD (solid triangle) and HP-β-CD (solidsquare) concentration on aqueous solubility of THC.

FIG. 2 shows the effect of RM-β-CD (solid triangle) and HP-β-CD (solidsquare) concentration on aqueous solubility of CBD.

FIG. 3 shows the dissolution profile of THC from a capsule containing1.0 mg of pure THC and 99 mg of lactose.

FIG. 4 shows the dissolution profile of THC from a capsule containing25.7 mg of RM-β-CD/THC-complex and 74.3 mg of lactose.

FIG. 5 shows the dissolution profile of THC from a capsule containing amixture of THC, RM-β-CD and lactose.

FIG. 6 shows the dissolution profile of THC from a tablet comprising afreeze-dried RM-β-CD/THC-complex.

FIG. 7 shows the dissolution profile of CBD from a capsule containing1.0 mg of pure CBD and 99 mg of lactose.

FIG. 8 shows the dissolution profile of CBD from a capsule containing13.4 mg of RM-β-CD/CBD-complex (equivalent to 1 mg of CBD) and 86.6 mgof lactose.

FIG. 9 shows the dissolution profile of CBD from a capsule containing amixture of CBD, RM-β-CD and lactose.

FIG. 10 shows the dissolution profile of CBD from a tablet comprising afreeze-dried RM-β-CD/CBD-complex.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the use of methylated CDs to improve theaqueous solubility, dissolution rate, absorption rate andbioavailability of classical cannabinoids.

The present invention is based on the finding that methylated β-CDsincrease the aqueous solubility of cannabinoids significantly morecompared to other CDs. Thus, high concentrations of cannabinoids inaqueous solution can achieved by the said methylated CDs. Byfreeze-drying a solution containing the said methylated β-CD andcannabinoid, the cannabinoids can be transformed to a homogenous powderwith good dissolution properties. In this powder the cannabinoids arecomplexed by the CD-molecules (i.e., the cannabinoid molecules areinside of the CD cavity, forming inclusion complexes) the dissolutionrate of the cannabinoids increasing due to the excellentsolubility/dissolution properties of the CD.

This novel finding can be utilized in a novel type of cannabinoidformulations. Cannabinoids are highly lipophilic compounds with poordissolution properties. In oral drug delivery the major problem ofcannabinoids is a high first-pass metabolism and poor dissolutionproperties. Thus, sublingual and buccal dosage forms are potentialalternatives for cannabinoid therapy due to circumvention of thefirst-pass metabolism in this manner of administration. The majorproblem in sublingual and buccal dosage forms is the low aqueousdissolution rate of cannabinoids. In the present innovation the poordissolution properties have been overcome by means of complex formationwith methylated β-CDs that significantly increases the dissolution rateof cannabinoids and allows the use of sublingual and buccal dosage formsof cannabinoids.

The cannabinoid/methylated β-CD complexes can also be utilized in otheroral formulations, such as in tablets or capsules, in order to improvethe dissolution rate and bioavailability of cannabinoids. In addition,the improved dissolution properties of cannabinoids in CD containingformulations can also be utilized in other drug administration routes ofcannabinoids, such as in pulmonary and nasal administration.

Compared to earlier findings, methylated β-CD improves the aqueoussolubility of cannabinoids more efficiently, imparting promisingdissolution properties for cannabinoids. Jarho et. al. (1998) showedthat the aqueous solubility of THC can be increased with HP-β-CD.However, the complexation of cannabinoids with methylated β-CD is moreefficient compared to HP-β-CD. This improves the pharmaceuticalusefulness of CDs significantly.

As discussed above, the bioavailability of THC is 6-20% after oraladministration. THC is commercially available as a capsule containing5-10 mg of THC (Marinol). Jarho et al. showed that with a 40% solutionof HP-β-CD, a 1 mg/ml solution of THC can be obtained. Thus, it can becalculated that 2 g of HP-β-CD is needed to establish a dosage formcontaining 5 mg of complexed THC. This is an amount that is too much fortablet formulations. According to the invention it has now been shownthat the same amount of THC can be complexed with 200 mg of RM-β-CD.

In sublingual and buccal formulations a smaller dose of cannabinoids canbe administered due to by-pass of the first pass metabolism. However,also in these applications methylated β-CDs offer superiorcharacteristics compared to, for example, HP-β-CD. As indicated above,for example, 400 mg of HP-β-CD would be needed to complex 1 mg of THC.The same formulation can be prepared with 25.7 mg of RM-β-CD whichincreases the usefulness of CD technology also in sublingual and buccaldrug formulations.

The novel inclusion complexes of the invention can be prepared inconventional manner, known to a person skilled in art. Such complexesare typically made by dissolving a selected cannabinoid in a selectedCD. The product is usually a mixture of cannabinoid/CD-complex,uncomplexed cannabinoid and uncomplexed CD. The amounts of cannabinoidsand CD are selected to give desired complexation efficiency which alsodepends on the complexation constant between cannabinoid and CD. Thecomplexation constant (K_(1:1), K_(1:2)) between cannabinoids and CDsare usually in a range of 1 M⁻¹ to 100 000 M⁻¹. Typically cannabinoidand CD are used in a weight ratio (dry weight to dry weight) rangingbetween 1:4 and 1:1000, such as 1:4 to 1:250. When the methylated CDsare used as a solution such a solution can contain 0.1 to 50% by weightof CD.

The formation of inclusion complex can be facilitated by using solvents,such as organic solvents, for example ethanol. The temperature can varyto some degree, but it is typically for convenience the ambienttemperature. Small amounts of water-soluble polymers, such ashydroxypropylmethylcellulose at elevated temperatures can also be usedto improve the complexation of cannabinoid with CDs.

After mixing, typically for 1-3 days, the solution obtained is allowedto come to an equilibrium, and can thereafter, if desired, befreeze-dried or spray-dried, to form a powder to be included in apharmaceutical preparation.

The cannabinoid CD inclusion complexes can also be prepared underheterogenous conditions (suspension) and in solid phase. These methodsinclude methods such as kneading, grinding, and the so-called slurrymethod. In solution, methods such as co precipitation and neutralizationcan be used to prepare the solid inclusion complexes.

The pharmaceutical preparation can be any suitable pharmaceuticalpreparation for oral, including sublingual and buccal, administration,or, for example, for nasal and/or pulmonary administration, but can alsobe a pharmaceutical preparation for e.g. parenteral, topical or rectaluse.

The pharmaceutical preparation according to the invention contains thesaid complex in pharmaceutically acceptable amounts together withpharmaceutically acceptable carriers, adjuvants or vehicles known in theart. The manufacture of such pharmaceutical formulations is well knownin the art.

Thus the pharmaceutical composition may be in a dosage form suitable fororal use, such as tablets, capsules, liquid dosage forms, such assuspensions, emulsions, syrups etc, or e.g. a powder for pulmonary use.All such formulations are made using per se known formulation techniquesand carriers, adjuvants and/or additives. Suitable vehicles for makingoral administration forms such as tablets or capsules are for examplestarch, lactose, sucrose, sorbitol, talc, stearates, etc. The complexaccording to the invention may also be administered parenterally, forexample using aqueous or oily suspensions, emulsions, or dispersionscontaining the active agent in combination with conventionalpharmaceutically acceptable excipients. Formulations for rectal use aree.g. suppositories containing the said complex in combination withcarrier substances suitable for rectal use.

Also contemplated within the invention is the topical administration ofthe complex, for which administration form creams, ointments, jellies,solutions, suspensions or the like are useful which contain apharmacologically active amount of the said complex together with a perse known pharmaceutically acceptable carrier or vehicle.

The therapeutic dose to be given to a patient in need of treatment willvary depending i.a. on the body weight and age of the patient, theparticular condition being treated as well as the manner ofadministration and are easily determined by a person skilled in the art.Generally a concentration of 0.01% to 5% of active agent, cannabinoid,in a suitable carrier would be sufficient for topical use, whereas adosage form for oral use of 0.1 mg to 5 g, typically 0.1 mg to 500 mgcannabinoid, to be given for example 1 to 4 times a day, would besuitable for most purposes.

The following examples illustrate the invention without limiting thesame in any way.

EXAMPLE 1

In this example the aqueous solubility studies of THC and CBD withRM-β-CD and HP-β-CD has been shown (FIG. 1. shows the effect of RM-β-CDand (▴) HP-β-CD (▪) concentration on aqueous solubility of THC; FIG. 2.shows the effect of RM-β-CD (▴) and HP-β-CD (▪) concentration on aqueoussolubility of CBD). Solubility studies show that RM-β-CD increases theaqueous solubility of both cannabinoids significantly more compared toHP-β-CD. AU the phase-solubility diagrams (cannabinoid concentration asa function of CD concentration) are Ap-type (Higuchi and Connors 1965)and calculated complexation constants for 1:1 and 1:2 inclusioncomplexes has been shown in Table 1.

TABLE 1 The calculated complexation constant for 1:1 (K_(1:1)) and 1:2(K_(1:2)) inclusion complexes of THC and CBD with RM-β-CD and HP-β-CD,respectively. Cannabinoid CD K_(1:1) (M⁻¹) K_(1:2) (M⁻¹) THC RM-β-CD 19563 38 HP-β-CD  4 222 58 CBD RM-β-CD 484 145  8 HP-β-CD 13 844 62

EXAMPLE 2

In this example the effect of RM-β-CD on dissolution characteristics ofTHC have been shown with four different THC formulations.

The powder containing THC/RM-β-CD inclusion complex was prepared bydissolving CBD in an aqueous RM-β-CD solution which was freeze-driedafter equilibration (2 days). The HPLC analysis of powder above showedthat 12.4 mg of the powder contained 1.0 mg of THC. All the experimentswere performed in 2% RM-β-CD dissolution medias (pH 6.6) to ensure thefree dissolution of THC.

FIG. 3 shows the dissolution profile (dissolved THC as a function oftime) of THC from the gelatine capsule containing 1.0 mg of pure CBD and99 mg of lactose (Mean ± SD, n=4). FIG. 4 shows the same data withcapsule containing 25.7 mg of RM-β-CD/THC-complex (equivalent to 1 mg ofTHC) and 74.3 mg of lactose (Mean±SD, n=4).

FIGS. 3 and 4 show that the complexation of THC with RM-β-CD increasessignificantly the dissolution rate of THC (observe the different timescale in the figures). With RM-β-CD/THC formulation CBDis fullydissolved in 5 minutes and the dissolution of THC is controlled by thedissolution rate of the capsule (FIG. 8). Without RM-β-CD thedissolution rate is much slower and THC is fully dissolved after 1 hour.

In order to study the effect of inclusion complex formation ondissolution of THC the dissolution studies were also performed with thegelatine capsule containing a physical mixture of THC (1.0 mg), RM-β-CD(25.7 mg) and lactose (74.3 mg). The results (FIG. 5, Mean±SD, n=3) showthat the physical mixture-formulation did not have an effect on thedissolution rate of THC. Thus, the inclusion complex formation betweenTHC and RM-β-CD is crucial for fast dissolution of THC.

The dissolution studies were also carried out with the tablet preparedfrom freeze-dried RM-β-CD/THC-complex. Tablets contained 25.7 mg ofRM-β-CD/THC-complex (equivalent to 1.0 mg of THC) power and 74.3 mg oflactose. The results (FIG. 6, Mean±SD, n=6)) show that THC is fullydissolved in 15 minutes, which is significantly faster compared to thegelatine capsule containing pure THC (FIG. 3).

In conclusion, the present results show that the complexation of THCwith RM-β-CD increases significantly the dissolution rate of THC.

EXAMPLE 3

In this example the effect of RM-β-CD on dissolution characteristics ofCBD have been shown also with four different CBD formulations.

The powder containing CBD/RM-β-CD inclusion complex was prepared bydissolving CBD in the aqueous RM-β-CD solution which was freeze-driedafter equilibration (2 days). The HPLC analysis of the powder aboveshowed that 12.4 mg of the powder contained 1.0 mg of CBD. All theexperiments were performed in 2% RM-β-CD dissolution medias (pH 6.6) toensure the free dissolution of CBD.

FIG. 7 shows the dissolution profile (dissolved CBD as a function oftime) CBD from the gelatine capsule containing 1.0 mg of pure CBD and 99mg of lactose (Mean±SD, n=6). FIG. 8 shows the same data with capsulecontaining 12.4 mg of RM-β-CD/CBD-complex (equivalent to 1 mg of CBD)and 86.6 mg of lactose (Mean±SD, n=6).

FIGS. 7 and 8 show that the complexation of CBD with RM-β-CD increasessignificantly the dissolution rate of CBD (observe the different timescale in the figures). With RM-β-CD/CBD formulation CBD is fullydissolved in 5 minutes and the dissolution of CBD is controlled by thedissolution rate of the capsule (FIG. 8). Without RM-β-CD thedissolution rate is much slower and CBD is fully dissolved after 3hours.

In order to study the effect of the inclusion complex formation on thefast dissolution of CBD the dissolution studies were also performed withthe gelatine capsule containing physical mixture of CBD (1.0 mg),RM-β-CD (12.4 mg) and lactose (86.6 mg). The results (FIG. 9; Mean±SD,n=6) show that physical mixture-formulation did not have an effect ondissolution rate of CBD. Thus, the inclusion complex formation betweenCBD and RM-β-CD is crucial for the fast dissolution of CBD.

The dissolution studies were also carried out with the tablet preparedfrom freeze-dried RM-β-CD/CBD-complex. The tablets contained 12.4 mg ofRM-β-CD/CBD-complex (equivalent to 1.0 mg of pure CBD) powder and 86.6mg of lactose. The results (FIG. 10, Mean±SD, n=6) show that CBD isfully dissolved in 15 minutes, which is significantly faster compared tothe gelatine capsule containing pure CBD (FIG. 7).

In conclusion the present results show that the complexation of CBD withRM-β-CD increases significantly the dissolution rate of CBD.

REFERENCES

-   Frömming K-H, Szejtli J: Cyclodextrins in pharmacy. Kluwer Academic    Publishers, Dortrecht, 1994.-   Higuchi T, Connors K A: Phase-solubility techniques. Adv. Anal.    Chem. Instr. 4: 117-212, 1965.-   Porcella A, Maxia C, Gessa G L, Pani L: The synthetic cannabinoid    WIN55212-2 decreases the intraocular pressure in human glaucoma    resistant to conventional therapies. Eur. J. Neurosci. 13: 409412,    2001.-   Pertwee, R G: Pharmacology of cannabinoid CB1 and CB2 receptors.    Pharmacol. Ther. 74: 129-180, 1997.-   Shoyama Y, Morimoto S, Nishioka I: Cannabis XV: preparation and    stability Δ⁹-tetrahydrocannabinol-β-cyclodextrin inclusion    complex. J. Nat. Prod. 46: 633-637, 1983.-   Song Z-H, Slowey C-A: Involvement of cannabinoid receptors in the    intraocular pressure lowering effects of WIN55212-2. J. Pharm. Exp.    Ther. 292: 136-139, 2000.-   Williamson E M, Evans F J: Cannabinoids in clinical practise. Drugs    60: 1303-1314, 2000.-   Zhang M-Q, Rees D C: A review of recent application of cyclodextrins    for drug discovery. Exp. Opin. Ther. Patents. 9:1697-1717, 1999.

1. A complex comprising: (A) RM-β-cyclodextrin, and (B) a cannabinoidselected from the group consisting of a tetrahydrocannabinol and acannabidiol.
 2. The complex according to claim 1, wherein thecannabinoid is a tetrahydrocannabinol.
 3. The complex according to claim1, wherein the cannabinoici is Δ⁹-tetrahydrocannabinol.
 4. The complexaccording to any one of claims 1, 2, or 3, wherein the cannabinoid andcyclodextrin are present in the complex in a weight ratio, based on dryweight, of 1:4-1:1000.
 5. A pharmaceutical composition comprising atherapeutically effective amount of the complex of any one of claims 1,2, or 3, and at least one pharmaceutically acceptable carrier, adjuvantor additive.
 6. The pharmaceutical composition according to claim 5,wherein said composition is an oral dosage composition.
 7. Thepharmaceutical composition according to claim 6, wherein saidcomposition is in the form of a tablet, a capsule, a solution, a sprayor a chewing gum.
 8. The pharmaceutical composition according to claim5, wherein said composition is a pulmonary or nasal dosage composition.9. The pharmaceutical composition according to claim 8, wherein saidcomposition is in the form of a solution, a spray, or a powder.
 10. Thepharmaceutical composition according to claim 6, wherein said oraldosage composition is suitable for sublingual or buccal administration.11. The pharmaceutical composition according to claim 5, wherein saidcomposition is a topical dosage composition.
 12. The pharmaceuticalcomposition according to claim 11, wherein said composition is a cream,an ointment, a jelly, a solution, or a suspension.
 13. Thepharmaceutical composition according to claim 12, wherein saidcomposition comprises 0.01% to 5% of cannabinoid.
 14. The complexaccording to claims 1, 2, or 3 wherein the cannabinoid and cyclodextrinare present in the complex in a weight ratio, based on dry weight, of1:4-1:250.
 15. A method of treatment of a subject comprisingadministering to a subject afflicted with or suffers from nausea,muscular spasms, multiple sclerosis, uterine cramps, bowel cramps, amovement disorder, pain, migraine headache, glaucoma, asthma,inflammation, insomnia, high blood pressure, cancer, anxiety,convulsions, depression or psychosis, an effective amount of the complexof claim 1, 2, or
 3. 16. The method according to claim 15, wherein saidcomplex is administered orally such that from 0.1 to 5 g of cannabinoidare administered per day.
 17. The method according to claim 16, whereinsaid complex is administered orally such that from 0.1 to 500 mg ofcannabinoid are administered per day.
 18. The method according to claim15, wherein said complex is topically administered.
 19. The methodaccording to claim 18, wherein said complex is in a composition selectedfrom the group consisting of a cream, an ointment, a jelly, a solution,or a suspension.
 20. The method according to claim 19, wherein saidcomposition comprises 0.01% to 5% of cannabinoid.